1. Field of the Invention
The present invention relates to dispersions, emulsions, microemulsions, gels and compositions including an organic iodized fluorocarbon compound, for biomedical use. Such compositions are useful notably in diagnosis, and particularly as contrast enhancement agents in radiography and scintigraphy.
2. Background of the Art
Conventional contrast enhancement agents utilized in diagnostic procedures are from the following classes: hydrosoluble agents, lipidic agents, or brominated perfluorocarbon agents. Each of these classes of agents has attendant problems. For example, iodinated hydrosoluble agents have a short intravenous persistence due to their rapid diffusion in the tissues. Therefore, the time in which the examination can be undertaken is significantly reduced, and successive injections are often necessary.
Moreover, these agents provoke side effects ranging from anaphylactic reactions to cardiovascular distress. See Deray et al. Diabetes and Metobolism 17:379-382 (1991) and Westhoff-Bleck et al. Drug Safety 6(1):28-36 (1991).
While lipidic contrast agents, such as Lipiodol (commercialized by Guerbet Laboratories), are less quickly diffused into the tissues, they form unstable emulsions of high viscosity. Further, the emulsions often form particle sizes of several microns, which can produce granulomas and provoke, in the case of an intravenous injection, fatty embolus. See Dictionnaire Vidal, p. 1562 (1992). Hepatic toxicity has also been observed for emulsions of lipidic iodinated products. See Mutzel et al. U.S. Pat. No. 4,367,216 and Wolf et al. U.S. Pat. No. 5,114,703. Accordingly, they can only be safely used in specific applications such as in lymphography or sialography.
Brominated perfluorocarbon contrast agents have also been used for contrast enhancement. For example, the Imagent product line from Alliance Pharmaceutical Corp. is based on brominated perfluorocarbon agents. These agents can be used in either the pure state or in the form of emulsions. Further, their intravenous persistence is longer than the hydrosoluble agents and they have reduced toxicity as compared to both the hydrosoluble and lipidic agents. See Long et al. Blood Substitutes, pp. 441-442 (Marcel Dekker Inc., N.Y. (1989)). However, their radiopaque constituent, perfluorooctyl bromide (Perflubron or PFOB), being bromine based, possesses reduced opacity under radiation as compared to that of iodine, for example. Therefore, higher doses are often necessary to achieve suitable contrast levels.
Iodinated perfluoroalkyated compounds have been studied for use as contrast enhancement agents. However, to date, most of these agents have proven too toxic for use in biomedical applications. See Long et al. in Preparations, Properties and Industrial Applications of Organofluorine Compounds p. 139, R. E. Banks, Ed. (Ellis Horword Ltd., Chichester, U.K., (1982)). They were essentially perfluoroalkylated compounds, iodinated at one of the chain termini. Compare, however, U.S. Pat. No. 4,367,216 to Mutzel et al., which discloses triiodinated 5-aminoisophthalic acid derivatives.
Accordingly, it would be beneficial to develop a contrast enhancement agent to improve upon the prior art and overcome and/or ameliorate some of the shortcomings presented thereby, such as high toxicity, limited persistence, and limited opacity.